Metabolism of N′ -nitrosonornicotine by cultured rat esophagus

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Abstract
The metabolism of N''-nitrosonornicotine (NNN, a tobacco specific carcinogen), an esophageal carcinogen, by organ cultured F-344 rat esophagus was investigated. The major metabolites were separated by HPLC (high pressure liquid chromatography) and were identified by comparison to standards as 4-hydroxy-1-(3-pyridyl)-1-butanone, 4-hydroxy-4-(3-pyridyl)-1-butanol and 4-oxo-4-(3-pyridyl)butyric acid from 2''-hydroxylation of NNN and 4-hydroxy-4-(3-pyridyl)-butyric acid from 5''-hydroxylation of NNN. .alpha.-Hydroxylation, which leads to electrophilic diazohydroxides, is the major pathway of metabolism of NNN in cultured F-344 rat esophagus. The extents of formation of the metabolites increased with time and the ratio of products resulting from 2''-hydroxylation to those resulting from 5''-hydroxylation was 4.3 after 1 h, 3.9 after 6 h, 3.4 after 24 h and 3.1 after 48 h. F-344 rat liver slices from the same animals produced metabolites of NNN with a 2''/5''-hydroxylation ratio of 1.4. The 2''/5''-hydroxylation ratio in cultured Syrian golden hamster esophagus was 0.3. These results, together with those of parallel studies of NNN metabolism in A/J mouse lung and Syrian golden hamster trachea indicate that among these tissues, F-344 rat esophagus has a unique ability to preferentially hydroxylate the 2''-position of NNN. The results suggest that 2''-hydroxylation is the key step in the metabolic activation of NNN in rat esophagus.

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